[a] Analgesic, Anti-inflammatory and Anti-pyretic Drugs
Non-narcotic analgesics, most of which are also known as non-steroidal anti-inflammatory drugs [NSAID], are widely administered orally in the treatment of mild to severe pain. Within this class, the compounds vary widely in their chemical structure and in their biological profiles as analgesics, anti-inflammatory agents and anti-pyretic agents. Aspirin, acetaminophen and phenacetin have long been among the most commonly used members of this group; more recently, however, a large number of alternative non-narcotic agents offering a variety of advantages over the earlier drugs have been developed. Tolerance or addiction to these drugs is not generally a problem with their continuous use in the treatment of pain or in the treatment of acute or chronic inflammatory states [notably, rheumatoid arthritis and osteoarthritis]; nevertheless, these drugs generally have a higher potential for adverse side-effects at the upper limits of their effective dose ranges. Moreover, above each drug's upper limit or ceiling, administration of additional drugs does not usually increase the analgesic or anti-inflammatory effect. Among the newer compounds in the non-narcotic analgesic/non-steroidal anti-inflammatory group are compounds such as diflunisal [Dolobid.RTM.], ibuprofen [Brufen.RTM.], naproxen [Naprosyn.RTM.], fenoprofen [Fenopron.RTM.], piroxicam [Feldene.RTM.], flurbiprofen, mefenamic acid [Ponstan.RTM.] and sulindac [Clinoril.RTM.]. See also Physicans' Desk Reference, 35th edition, 1981, and The Merck Index, ninth edition, Merck & Co., Rahway, New Jersey (1976), for information on specific non-steroidal anti-inflammatory agents. Also see, generally, Wiseman, "Pharmacological Studies with a New Class of Non-steroidal Anti-Inflammatory Agents--Tbe Oxicams--With Special Reference to Piroxicam (Feldene.RTM.)", The American Journal of Medicine, Feb. 16, 1982:2-8; Foley et al, The Management of Cancer Pain, Volume II--The Rational Use of Analgesics in the Management of Cancer Pain, Hoffman-La Roche Inc., 1981; and Cutting's Handbook of Pharmacology, sixth edition, ed. T. Z. Czaky, M.D. Appleton-Century-Crofts, New York, 1979, Chapter 49: 538-550.
The exact mechanism of action of this group of compounds and the relationship between chemical structure and analgesic, anti-inflammatory and anti-pyretic effect of these compounds are not yet fully understood despite the fact that some of these products, like aspirin and acetaminophen have been in use for many years. The recent contributions of John Vane in "Towards a better aspirin", Nature Volume 367, Jan. 20, 1993, pages 215 to 216 and of the authors referred to therein, which links such activities to the ability of these compounds to inhibit the enzyme known as cyclooxygenase [COX] of which two, and possibly three, isoforms exist, will no doubt play an important role in the future understanding of the mode of action and properties of this group of compounds.
Narcotic analgesics are often used when pain control with non-narcotic analgesics is ineffective. While the drugs in this group vary considerably in their chemical structures and pharmacological properties, almost all suffer the disadvantages of tolerance and possible addiction with continued usage. Within the narcotic analgesic group, the drugs can be classified as narcotic agonists or narcotic antagonists. Narcotic agonists include the morphine group, the pethidine group and the methadone group. While some narcotic antagonists are pure antagonists [which are not analgesics], other narcotic antagonists are agonist-antagonists [i.e. antagonists with analgesic properties]; the agonist-antagonists are generally categorised as morphine-like or nalorphine-like]. Many of the narcotic analgesics are not effective orally, but are rather used parenterally. The orally active narcotic analgesics include such compounds as codeine, oxycodone, pethidine, dextro-propoxyphene [Doloxene.RTM.], methadone, propiram, buprenorphine, pentazocine [Sosegon.RTM.] and nalbuphine [Nubain.RTM.]. For more specific information on these compounds, see Physicians' Desk Reference, 35th edition, 1981, and The Merck Index, ninth edition, Merck & Co., Inc., Rahway, New Jersey 1976). Also see, generally, the Foley et al reference cited hereinabove and Cutting's Handbook of Pharacology, sixth edition, ed. T. Z. Czaky, M.D., Appleton-Century-Crofts, New York, 1979, Chapter 50: 551-566.
[b] Potentiation of Analgesic, Anti-inflammatory and Anti-pyretic Drugs
It has been suggested in South African Patent 83/5324 in the name of Sunshine, Laska and Siegel that caffeine may be used to hasten the onset and to enhance the analgesic response of the analgesic, anti-inflammatory and anti-pyretic agents referred to above.
[c] Nitrous Oxide Gas
Nitrous oxide [N.sub.2 O] is a natural gas which is also produced synthetically. It is also known by the trivial name "laughing gas". It has been in use for many years as an inhalation anaesthetic and analgesic, particularly in dentistry.
Nitrous oxide has been reported to have a synergistic or potentiating effect on halothane and other gaseous anaesthetics [See Goodman & Gilman's The Pharmacological Basis of Therapeutics 8th Ed. 1990 pp. 298-300].
Since such known synergism or potentiation is based on the use of nitrous oxide administered by inhalation, and since the use of nitrous oxide on its own as an anaesthetic and analgesic has likewise been in the form of an inhalation agent, the use of nitrous oxide for all these purposes have been confined to hospitalised patients or, at best, to treatments carried out by medical practitioners in their consulting rooms, or treatments carried out by or under supervision of a nurse in charge of a home-care patient.
[d] Nitrous Oxide in Solution
Nitrous oxide is known to be soluble in water and it has been reported that at 20.degree. C. and 2 atm pressure one litre of the gas dissolves in 1,5 litres of water, see The Merck Index 10th Ed. p. 6499.
In the applicant's PCT patent application PCT/EP93/01405 published under number WO 93/25213 and co-pending patent applications derived therefrom and its South African counterpart Patent 94/3895 it disclosed dermatological compositions comprising nitrous oxide as an active ingredient in compositions which also include one or more essential fatty acids or lower alkyl esters thereof, and, optionally, one or more supplementary active ingredients selected from the group consisting of coal tar solution, collagen, lanolin, nicotinamide, nicotinic acid, lanolin, vitamin E, methyl salicylate, arnica and an H-antagonist antihistamine such as diphenylhydramine hydrochloride. In those compositions nitrous oxide is dissolved in water.
Nitrous oxide is also known for its use as a propellant gas, mainly as a substitute for propellant gases such as chlorofluorocarbons, and more particularly to produce a food product mousse such as whipped cream or chocolate mousse or quick-breaking foams for hair treatment preparations. See in this regard U.K. Patent 1033299, U.K. Patent 1105919 and European Patent Application EPA-0123827. None of these prior publications suggest that the nitrous oxide gas, plays any other role than a physical one, i.e. to expand on being depressurised and thereby to create a mousse or a foam. In fact it is typically regarded as an inert in these applications and useful due to the fact that it is colourless, odourless and tasteless but soluble in water and oils.
There appears to be no suggestion in the literature that aqueous solutions of nitrous oxide might have any analgesic or anaesthetic effect on man or animals. As far as the present inventors know it has also never been suggested that nitrous oxide may be used in conjunction with analgesic, anti-inflammatory or anti-pyretic substances to contribute to, or to hasten or to enhance their pharmacological action.